Alcohol dependence is the most prevalent psychiatric disorder, and also one of the most costly health care problems faced by society. Although there are three medications approved by the Food and Drug Administration (FDA) to treat alcoholism all three have limitations, so the development of new medications is of high clinical importance. Nicotine and alcohol dependence are linked by a high rate of comorbidity, a synergistic effect of nicotine and ethanol use and a common neurobiology. In fact, acetylcholine nicotinic receptors (nAChR), which are important in nicotine dependence may also play a crucial role in alcohol dependence. Preclinical and human laboratory studies have suggested that a drug known to block nicotine receptors, mecamylamine hydrochloride (Inversine), decreases alcohol use and craving. We conducted a pilot study evaluating the effects of mecamylamine on ethanol use in alcohol dependent individuals, approximately 60% of whom were smokers. Our preliminary data suggests that there is a significant interaction between smoking status and medication group on the alcohol use outcome heavy drinking days with a large effect size; there is a trend toward significance in the outcome drinking days where non-smokers treated with mecamylamine had better outcomes compared to non-smokers treated with placebo. No subjects spontaneously reported quitting smoking. This study is first known treatment study in alcohol dependent patients. Methods: One hundred and eighty-four individuals with alcohol dependence will be randomly assigned to receive either a standard dose of mecamylamine (10 mg daily) or a matching placebo every day for a total of twelve weeks. Outcomes include ethanol intake as measured by the Time Line Followback Method, craving as measured by the Obsessive Compulsive Drinking Scale, psychiatric distress and side effect burden. In addition, we will evaluate smoking behavior in smokers who are not trying to abstain from smoking. We hypothesize that mecamylamine will significantly reduce heavy drinking days over time compared to placebo, and that this effect will be moderated by smoking status such that the effect will be stronger in non-smokers. We will also evaluate smoking use outcomes and use this study as a platform to conduct future studies. This is the first study conducted to evaluate mecamylamine as a potential pharmacotherapeutic agent for alcohol dependence.